tbuckley/cabot-search huggingface dataset:
Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects
Authors: Kim Han, Komudi Singh, Allison M. Meadows, Rahul Sharma, Shahin Hassanzadeh, Jing Wu, Haley Goss-Holmes, Rebecca D. Huffstutler, Heather L. Teague, Nehal N. Mehta, Julian L. Griffin, Rong Tian, Javier Traba, Michael N. Sack
Journal: Cell Reports Medicine (2023)

To evaluate whether nicotinamide adenine dinucleotide-positive (NAD+) boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. NR administration increases sqstm1 and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2 and the Nrf2-dependent gene, sqstm1, diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD+ boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4+ T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1, and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD+ boosting in CD4+ T cell-linked inflammation.
Improving outcomes in intracerebral hemorrhage through microglia/macrophage-targeted IL-10 delivery with phosphatidylserine liposomes
Authors: Ranran Han, Xi Lan, Zheng Han, Honglei Ren, Safiya Aafreen, Wenshen Wang, Zhipeng Hou, Tianyue Zhu, Andrew Qian, Xiaoning Han, Raymond C. Koehler, Guanshu Liu
Journal: Biomaterials (2023)
Neural dynamics in the limbic system during male social behaviors
Authors: Zhichao Guo, Luping Yin, Veronica Diaz, Bing Dai, Takuya Osakada, Julieta E. Lischinsky, Jonathan Chien, Takashi Yamaguchi, Ashley Urtecho, Xiaoyu Tong, Zhe S. Chen, Dayu Lin
Journal: Neuron (2023)
Pushing forward in sarcoma with a new TCR targeting NY-ESO-1
Authors: Rusul Al-Marayaty, Seth M. Pollack
Journal: Cell Reports Medicine (2023)

A phase 1 trial demonstrating the safety and efficacy of a novel NY-ESO-1-specific TCR-T cells by Pan et al.1 is a major step forward for adoptive T cell therapy in the clinical practice of advanced soft tissue sarcomas.
A CSF-1R-blocking antibody/IL-10 fusion protein increases anti-tumor immunity by effectuating tumor-resident CD8+ T cells
Authors: Yao-Wen Chang, Huey-Wen Hsiao, Ju-Pei Chen, Sheue-Fen Tzeng, Chin-Hsien Tsai, Chun-Yi Wu, Hsin-Hua Hsieh, Santiago J. Carmona, Massimo Andreatta, Giusy Di Conza, Mei-Tzu Su, Pandelakis A. Koni, Ping-Chih Ho, Hung-Kai Chen, Muh-Hwa Yang
Journal: Cell Reports Medicine (2023)

Strategies to increase intratumoral concentrations of an anticancer agent are desirable to optimize its therapeutic potential when said agent is efficacious primarily within a tumor but also have significant systemic side effects. Here, we generate a bifunctional protein by fusing interleukin-10 (IL-10) to a colony-stimulating factor-1 receptor (CSF-1R)-blocking antibody. The fusion protein demonstrates significant antitumor activity in multiple cancer models, especially head and neck cancer. Moreover, this bifunctional protein not only leads to the anticipated reduction in tumor-associated macrophages but also triggers proliferation, activation, and metabolic reprogramming of CD8+ T cells. Furthermore, it extends the clonotype diversity of tumor-infiltrated T cells and shifts the tumor microenvironment (TME) to an immune-active state. This study suggests an efficient strategy for designing immunotherapeutic agents by fusing a potent immunostimulatory molecule to an antibody targeting TME-enriched factors.
Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease
Authors: Ruth Hanssen, Chiara Auwerx, Maarja Jõeloo, Marie C. Sadler, Elana Henning, Julia Keogh, Rebecca Bounds, Miriam Smith, Helen V. Firth, Zoltán Kutalik, I. Sadaf Farooqi, Alexandre Reymond, Katherine Lawler
Journal: Cell Reports Medicine (2023)

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10
Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS
Authors: Zhijie Wu, Shouguo Gao, Qingyan Gao, Bhavisha A. Patel, Emma M. Groarke, Xingmin Feng, Ash Lee Manley, Haoran Li, Daniela Ospina Cardona, Sachiko Kajigaya, Lemlem Alemu, Diego Quinones Raffo, Amanda K. Ombrello, Marcela A. Ferrada, Peter C. Grayson, Katherine R. Calvo, Daniel L. Kastner, David B. Beck, Neal S. Young
Journal: Cell Reports Medicine (2023)

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a pleiotropic, severe autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. To elucidate VEXAS pathophysiology, we performed transcriptome sequencing of single bone marrow mononuclear cells and hematopoietic stem and progenitor cells (HSPCs) from VEXAS patients. HSPCs are biased toward myeloid (granulocytic) differentiation, and against lymphoid differentiation in VEXAS. Activation of multiple inflammatory pathways (interferons and tumor necrosis factor alpha) occurs ontogenically early in primitive hematopoietic cells and particularly in the myeloid lineage in VEXAS, and inflammation is prominent in UBA1-mutated cells. Dysregulation in protein degradation likely leads to higher stress response in VEXAS HSPCs, which positively correlates with inflammation. TCR usage is restricted and there are increased cytotoxicity and IFN-γ signaling in T cells. In VEXAS syndrome, both aberrant inflammation and myeloid predominance appear intrinsic to hematopoietic stem cells mutated in UBA1.
Bioengineered human tissue regeneration and repair using endogenous stem cells
Authors: Jiao Wei, Daniel T. Baptista-Hon, Zi Wang, Gen Li, Tanja Herrler, Chuanchang Dai, Kai Liu, Baofu Yu, Xiaoxue Chen, Mei Yang, Dong Han, Yuanxu Gao, Ru-Lin Huang, Lifei Guo, Kang Zhang, Qingfeng Li
Journal: Cell Reports Medicine (2023)

We describe a general approach to produce bone and cartilaginous structures utilizing the self-regenerative capacity of the intercostal rib space to treat a deformed metacarpophalangeal joint and microtia. Anatomically precise 3D molds were positioned on the perichondro-periosteal or perichondral flap of the intercostal rib without any other exogenous elements. We find anatomically precise metacarpal head and auricle constructs within the implanted molds after 6 months. The regenerated metacarpal head was used successfully to surgically repair the deformed metacarpophalangeal joint. Auricle reconstructive surgery in five unilateral microtia patients yielded good aesthetic and functional results. Long-term follow-up revealed the auricle constructs were safe and stable. Single-cell RNA sequencing analysis reveal early infiltration of a cell population consistent with mesenchymal stem cells, followed by IL-8-stimulated differentiation into chondrocytes. Our results demonstrate the repair and regeneration of tissues using only endogenous factors and a viable treatment strategy for bone and tissue structural defects.
Phase 1 clinical trial to assess safety and efficacy of NY-ESO-1-specific TCR T cells in HLA-A∗02:01 patients with advanced soft tissue sarcoma
Authors: Qiuzhong Pan, Desheng Weng, Jiayong Liu, Zhaosheng Han, Yusheng Ou, Bushu Xu, Ruiqing Peng, Yi Que, Xizhi Wen, Jing Yang, Shi Zhong, Lun Zeng, Aiyuan Chen, Haiping Gong, Yanmei Lin, Jiewen Chen, Ke Ma, Johnson Y.N. Lau, Yi Li, Zhengfu Fan, Xing Zhang
Journal: Cell Reports Medicine (2023)

New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cell receptor (TCR) T cell therapy is effective in tumors with NY-ESO-1 expression, but a safe and effective TCR-T cell therapeutic protocol remains to be improved. Here, we report a phase 1 investigational new drug clinical trial with TCR affinity-enhanced specific T cell therapy (TAEST16001) for targeting NY-ESO-1. Enrolled patients receive TAEST16001 cell infusion after dose-reduced lymphodepletion with cyclophosphamide (15 mg/kg/day × 3 days) combined with fludarabine (20 mg/m2/day × 3 days), and the TCR-T cells are maintained with low doses of interleukin-2 injection post-adoptive transfer. Analysis of 12 patients treated with the regimen demonstrates no treatment-related serious adverse events. The overall response rate is 41.7%. The median progression-free survival is 7.2 months, and the median duration of response is 13.1 months. The protocol of TAEST16001 cells delivers a safe and highly effective treatment for patients with advanced soft tissue sarcoma (ClinicalTrials.gov: NCT04318964).
Safety and immunogenicity of SARS-CoV-2 self-amplifying RNA vaccine expressing an anchored RBD: A randomized, observer-blind phase 1 study
Authors: Wataru Akahata, Takashi Sekida, Takuto Nogimori, Hirotaka Ode, Tomokazu Tamura, Kaoru Kono, Yoko Kazami, Ayaka Washizaki, Yuji Masuta, Rigel Suzuki, Kenta Matsuda, Mai Komori, Amber L. Morey, Keiko Ishimoto, Misako Nakata, Tomoko Hasunuma, Takasuke Fukuhara, Yasumasa Iwatani, Takuya Yamamoto, Jonathan F. Smith, Nobuaki Sato
Journal: Cell Reports Medicine (2023)

VLPCOV-01 is a lipid nanoparticle-encapsulated self-amplifying RNA (saRNA) vaccine that expresses a membrane-anchored receptor-binding domain (RBD) derived from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. A phase 1 study of VLPCOV-01 is conducted (jRCT2051210164). Participants who completed two doses of the BNT162b2 mRNA vaccine previously are randomized to receive one intramuscular vaccination of 0.3, 1.0, or 3.0 μg VLPCOV-01, 30 μg BNT162b2, or placebo. No serious adverse events have been reported. VLPCOV-01 induces robust immunoglobulin G (IgG) titers against the RBD protein that are maintained up to 26 weeks in non-elderly participants, with geometric means ranging from 5,037 (95% confidence interval [CI] 1,272–19,940) at 0.3 μg to 12,873 (95% CI 937–17,686) at 3 μg compared with 3,166 (95% CI 1,619–6,191) with 30 μg BNT162b2. Neutralizing antibody titers against all variants of SARS-CoV-2 tested are induced. VLPCOV-01 is immunogenic following low-dose administration. These findings support the potential for saRNA as a vaccine platform.
METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy
Authors: Yasi Pan, Huarong Chen, Xiang Zhang, Weixin Liu, Yanqiang Ding, Dan Huang, Jianning Zhai, Wenchao Wei, Jun Wen, Danyu Chen, Yunfei Zhou, Cong Liang, Nathalie Wong, Kwan Man, Alvin Ho-Kwan Cheung, Chi Chun Wong, Jun Yu
Journal: Cell Reports Medicine (2023)

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy of NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation, while Mettl3 knockout exerted the opposite effect in mice. Single-cell RNA sequencing revealed that METTL3 suppressed antitumor immune response by reducing granzyme B (GZMB+) and interferon gamma-positive (IFN-γ+) CD8+ T cell infiltration, thereby facilitating immune escape. Mechanistically, METTL3 mediates sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters that impair CD8+ T cell function in the tumor microenvironment. Targeting METTL3 by single-guide RNA, nanoparticle small interfering RNA (siRNA), or pharmacological inhibitor (STM2457) in combination with anti-programmed cell death protein 1 (PD-1) synergized to reinvigorate cytotoxic CD8+ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.
Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability
Authors: Yuqing Yan, Zhenhua Wang, Yi-Lu Zhou, Ziyun Gao, Lijun Ning, Ying Zhao, Baoqin Xuan, Yanru Ma, Tianying Tong, Xiaowen Huang, Muni Hu, Jing-Yuan Fang, Zhe Cui, Haoyan Chen, Jie Hong
Journal: Cell Reports Medicine (2023)

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance
Authors: Tingjin Chen, Zhi-Gang Xu, Jie Luo, Rajesh Kumar Manne, Zhengyu Wang, Che-Chia Hsu, Bo-Syong Pan, Zhen Cai, Pei-Jane Tsai, Yau-Sheng Tsai, Zhong-Zhu Chen, Hong-yu Li, Hui-Kuan Lin
Journal: Cell Metabolism (2023)
Selective targeting of IL2Rβγ combined with radiotherapy triggers CD8- and NK-mediated immunity, abrogating metastasis in HNSCC
Authors: Jacob Gadwa, Maria Amann, Thomas E. Bickett, Michael W. Knitz, Laurel B. Darragh, Miles Piper, Benjamin Van Court, Sanjana Bukkapatnam, Tiffany T. Pham, Xiao-Jing Wang, Anthony J. Saviola, Laura Codarri Deak, Pablo Umaña, Christian Klein, Angelo D’Alessandro, Sana D. Karam
Journal: Cell Reports Medicine (2023)

The implementation of cancer immunotherapies has seen limited clinical success in head and neck squamous cell carcinoma (HNSCC). Interleukin-2 (IL-2), which modulates the survival and functionality of lymphocytes, is an attractive target for new immunotherapies but one that is limited by presence of regulatory T cells (Tregs) expressing the high-affinity IL-2Rα. The bispecific immunocytokine PD1-IL2v preferentially delivers IL-2 signaling through IL-2Rβγ on PD-1-expressing cells. Selectively targeting the intermediate-affinity IL-2Rβγ can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting the negative regulation of IL-2Rα activation on Tregs. Using radiation therapy (RT) in combination with PD1-IL2v improves local tumor control and survival, and controls metastatic spread in orthotopic HNSCC tumor models. PD1-IL2v drives systemic activation and expansion of circulating and tumor-infiltrating cytotoxic T cells and NK cells while limiting Treg-mediated immunosuppression. These data show that PD1-L2v induces durable systemic tumor control in HNSCC.
Steroid 5α-Reductase 2 Deficiency*
Authors: JEAN D. WILSON, JAMES E. GRIFFIN, DAVID W. RUSSELL
Journal: Endocrine Reviews (1993)

BETWEEN 1968 and 1973 a large body of evidence accumulated in our laboratory and by others demonstrated that the conversion of testosterone to dihydrotestosterone plays a crucial role in androgen action, including virilization of the external genitalia in male embryos (reviewed in Ref. 1). We had postulated that mutations that impair dihydrotestosterone formation might be the cause of some cases of human male pseudohermaphroditism (2), and a candidate disorder for 5α-reductase deficiency was the rare autosomal recessive disorder termed pseudovaginal perineoscrotal hypospadias (3–7). In 1974 two siblings with pseudovaginal perineoscrotal hypospadias were ascertained in Dallas, and as the result of endocrine, phenotypic, and enzymatic studies it was established that these sisters did have a defect in 5 α-reductase activity (8). At the same time an extensive family from the Dominican Republic was described in whom male pseudohermaphroditism was also due to impairment of the conversion of testosterone to dihydrotestosterone (9, 10). In the intervening years many additional patients have been described, and the pathogenesis of this disorder has been explored in considerable detail, culminating in the cloning of two genes that encode steroid 5α-reductase isoenzymes (11–13). 5α-Reductase deficiency is of interest not because of its frequency (it is rare) but because of its importance for understanding the mechanism of androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior.
The <scp>CAR‐HEMATOTOX</scp> score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory <scp>MCL</scp>
Authors: Kai Rejeski, Yucai Wang, Omar Albanyan, Javier Munoz, Pierre Sesques, Gloria Iacoboni, Lucia Lopez‐Corral, Isabelle Ries, Veit L. Bücklein, Razan Mohty, Martin Dreyling, Aliyah Baluch, Bijal Shah, Frederick L. Locke, Georg Hess, Pere Barba, Emmanuel Bachy, Yi Lin, Marion Subklewe, Michael D. Jain
Journal: American Journal of Hematology (2023)

Abstract CD19‐directed CAR T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu‐cel. Furthermore, we report associations between the baseline CAR‐HEMATOTOX (HT) score and toxicity events, non‐relapse mortality (NRM), and progression‐free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HT low (score 0–1) while 47 patients were HT high (score ≥2). The HT high cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p &lt; .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1‐year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HT high patients experienced inferior 90‐day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not‐reached, p &lt; .0001), and OS (median 26 months vs. not‐reached, p &lt; .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu‐cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.
A national evaluation of adjuvant chemotherapy in pT4N0M0 colon cancer from the National Cancer Database
Authors: Thais Reif de Paula, Deborah S Keller
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background T stage is a prognostic biomarker for overall survival in colon cancer and pathologic T4 disease is a high-risk characteristic. Adjuvant chemotherapy is recommended to improve overall survival in pT4N0M0, but compliance with guidelines is unknown. We aimed to evaluate adjuvant chemotherapy use and impact on overall survival in pT4N0M0 colon cancer. Methods The National Cancer Database was reviewed for pT4N0M0 colon adenocarcinomas undergoing curative surgical resection (2010-2017). Cases were stratified into no adjuvant chemotherapy and adjuvant chemotherapy cohorts. Moderated multiple regression assessed factors associated with no AC. Kaplan–Meier and Cox regression assessed overall survival in propensity-score matched cohorts. The main outcome measures were adjuvant chemotherapy use, factors associated with adjuvant chemotherapy, and impact on overall survival. Results Of 11 847 cases, 62.4% (n = 7391) received no adjuvant chemotherapy. With private insurance, comorbidities or income do not affect adjuvant chemotherapy use. Medicare cases with a Charlson–Deyo comorbidity index of 0 (odds ratio [OR] = 0.861, 95% confidence interval [CI] = 0.760 to 0.975; P = .019) and Medicare payors with high income (OR = 0.813, 95% CI = 0.690 to 0.959; P = .014) were associated with adjuvant chemotherapy. Medicaid Charlson–Deyo comorbidity index 0 (OR = 1.374, 95% CI = 1.125 to 1.679; P = .002) and uninsured Charlson–Deyo comorbidity index 0 (OR = 1.351, 95% CI = 1.120 to 1.629; P = .002) were associated with no adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved 5-year overall survival (71.7% vs 56.4%; P &amp;lt; .001; adjusted hazard ratio = 0.543, 95% CI = 0.499 to 0.590; P &amp;lt; .001). Conclusion Although adjuvant chemotherapy is associated with improved overall survival, compliance is low. There is a complex relationship between payor, income, comorbidity, and adjuvant chemotherapy receipt. Medicare patients with no comorbidities or higher income have better adjuvant chemotherapy use. With private insurance, adjuvant chemotherapy compliance is not affected by comorbidities or income, whereas Medicaid and uninsured patients with no comorbidities have poor compliance. Future work could target these disparities for equitable care.
Error in Figure 2B
Journal: JAMA Network Open (2023)

James C. H. Chow, MBChB, MSc; Wah Cheuk, MBBS; William C. S. Cho, PhD; Chi-Fai Wong, PhD; Dennis W. Y. Au, MSc; Anthony H. P. Tam, MPH; Rachel C. W. Wong, PhD; Jeffrey C. H. Chan, MBBS; Simon C. C. Law, MBBS; Roger K. C. Ngan, MBBS; Kam-Hung Wong, MBChB; Ka-Man Cheung, MBChB